Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Molecular Oncology and Biomarkers Program, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, School of Medicine, Aurora, CO, USA.
Cancer Lett. 2019 Apr 1;446:62-72. doi: 10.1016/j.canlet.2019.01.010. Epub 2019 Jan 18.
Bone metastasis is a major cause of prostate cancer (PCa) mortality. Although docetaxel chemotherapy initially extends patients' survival, in most cases PCa becomes chemoresistant and eventually progresses without a cure. In this study, we developed a novel small-molecule compound BKM1972, which exhibited potent in vitro cytotoxicity in PCa and other cancer cells regardless of their differences in chemo-responsiveness. Mechanistic studies demonstrated that BKM1972 effectively inhibited the expression of anti-apoptotic protein survivin and membrane-bound efflux pump ATP binding cassette B 1 (ABCB1, p-glycoprotein), presumably via signal transducer and activator of transcription 3 (Stat3). BKM1972 was well tolerated in mice and as a monotherapy, significantly inhibited the intraosseous growth of chemosensitive and chemoresistant PCa cells. These results indicate that BKM1972 is a promising small-molecule lead to treat PCa bone metastasis and overcome docetaxel resistance.
骨转移是前列腺癌（PCa）患者死亡的主要原因。尽管多西他赛化疗最初延长了患者的生存时间，但在大多数情况下，PCa 会产生耐药性，最终在没有治愈方法的情况下进展。在这项研究中，我们开发了一种新型小分子化合物 BKM1972，它在体外对 PCa 和其他癌细胞具有强大的细胞毒性，而与它们对化疗的敏感性差异无关。机制研究表明，BKM1972 可有效抑制抗凋亡蛋白 survivin 和膜结合外排泵 ATP 结合盒 B1（ABCB1，p-糖蛋白）的表达，推测是通过信号转导和转录激活因子 3（Stat3）。BKM1972 在小鼠中耐受良好，作为单一疗法，可显著抑制化疗敏感和耐药 PCa 细胞的骨内生长。这些结果表明，BKM1972 是一种很有前途的小分子药物，可用于治疗 PCa 骨转移并克服多西他赛耐药性。
